Intrathymic T cell development proceeds through receptor- controlled checkpoints at which cells with properly assembled T cell receptors (TCR) are rescued from programmed cell death, expand and/or undergo further differentiation. Differentiation is controlled by transcription factors such as Notch1-dependent CSL, Ikaros, b-catenin-dependent TCF1 as well as basic helix loop helix (bHLH) proteins encoded by E2A and HEB genes. Some of the transcription factors control the assembly of the pre-TCR and signaling by the pre-TCR can regulate the function of certain transcription factors. While the binding of E47/HEB heterodimers to E-boxes in the regulatory region of several genes is believed to induce differentiation at the expense of proliferation, interference with that process is believed to result in proliferation at the expense of differentiation. Within this frame we will address the hypotheses that 1) Lymphomagenic abnormalities in gene expression synergize with the pre-TCR in generating T-ALL, 2) that known abnormalities in gene expression resulting in lymphoma affect cell cycle/survival of developing T cells, 3) that in the generation of T-ALL initial abnormalities in gene expression must be followed by further genetic changes, and 4) that similar molecular pathways are involved in murine and human T-ALL over expressing TALl.